This is the second competitive renewal application for this Program Project Grant. During the first two cycles, the focus has been on the molecular and cellular pathways that regulate the balance of Thi and Th2 cytokine patterns. This Program Project combines the expertise of two institutions, The University of Vermont (UVM) and the nearby Trudeau Institute. The UVM investigators have expertise is cell signaling, immunogenetics, and viral immunology, whereas the Trudeau investigators have strength in immune memory and in vivo infectious models. The renewal application makes an intentional application of our previous studies to in vivo infectious diseases. The central theme is the process by which infectious agents engage the innate immune system to influence the generation and fate of effector CD4 T cells. Of particular interest is the interface between innate and adaptive immune responses. Project 1 (Dr. Cory Teuscher) studies newly discovered roles for histamine and the four histamine receptors expressed by CD4 T cells during the transition from naive to effector to memory CD4 T cell, as well as promoting Th1 or Th2 cytokine profiles. Project 2 (Dr. Ralph Budd) examines y5 T cell in humans and mice in response to infection, their ability to recognize non-polymorphic CD1 molecules, which are upregulated following interactions of infectious organisms. In turn, the yST cells activate dendritic cells to produce cytokines and costimulatory molecules that are important to the activation of naive CD4 T cells. Project 3 (Dr. Mercedes Rincon) examines the role of IL-6 in upregulating IL-21 by CD4 T cells, which promotes antibody production and survival by B cells. This will be applied to the influenza model. Project 4 (Dr. Susan Swain) integrates aspects of the other projects into a study of the regulation of CD4 effector cell fate by antigen re-exposure, and by the inflammatory cytokine IL-6, as well as the autocrine T cell factors IL-2 and IL-21 they induce. This project will define the death pathways in CD4 effector contraction, and the impact on the quality and quantity of remaining memory T cells.